Figure 2. Signaling pathways activated by IL-21. Figure 2. Signaling pathways activated by IL-21. IL-21 activates JAK-STAT, PI 3-kinase (PI3K), and MAP kinase (MAPK) pathways. STAT3 plays a major role in the biological actions of IL-21, but STAT1 also contributes to IL-21-regulated gene expression. Opposing actions of STAT1 and STAT3 are important for fine-tuning IL-21’s functions. The importance of IL-21-activated STAT5 is not known. MAPK and PI3K pathways contribute to the proliferative effect of IL-21. In T cells, after IL-21 stimulation, optimal STAT3-mediated gene regulation requires functional cooperation with IRF4, which binds together with AP-1 family proteins (predominately BATF and JUN family proteins), to regulate genes containing AP1-IRF4 composite elements (AICEs). AhR can also cooperate with STAT3 for gene regulation in T cells after IL-21 stimulation. Additional transcription factors (TFs) and co-factors may also be involved. How to cite: Leonard WJ and Wan CK 2016 IL-21 Signaling in Immunity [version 1; referees: 3 approved] F1000Research 2016, 5:224 (doi: 10.12688/f1000research.7634.1) Leonard WJ and Wan CK 2016 [version 1; referees: 3 approved] F1000Research 2016, 5:224 (doi: 10.12688/f1000research.7634.1)